Rizzieri Looks at Long-Term Efficacy of Combination Therapy in DLBCL

Publication
Article
Peers & Perspectives in OncologyFebruary II, 2024
Volume 2
Issue 3
Pages: 11

At a live virtual event, David Rizzieri, MD, CPE, provided commentary on the landscape of treatment for patients with relapsed/refractory diffuse large B-cell lymphoma (DLBCL).

Rizzieri

David Rizzieri, MD, CPE

Senior Vice President

System Physician Executive

Hematology and Oncology

Novant Health Agnes B. and Edward I. Weisiger Cancer Institute

At a live virtual event, David Rizzieri, MD, CPE, provided commentary on the landscape of treatment for patients with relapsed/ refractory diffuse large B-cell lymphoma (DLBCL). He highlighted the importance of understanding all the data for the options physicians have, knowing that something may show great responses early on but not have long-term durability. This is why the data from the multicenter, open-label, single arm, phase 2 L-MIND (NCT02399085) study are important to note when looking to treat patients for whom 1 or more lines of prior therapy failed. These data showed long-term survival after 5 years of treatment and a toxicity profile that was manageable after handling tougher upfront adverse events.

LOOKING AT THE GUIDELINES

RIZZIERI: I’m old enough to remember...in the early 90s...that we all thought the third-generation regimens we used at the time were going to be better than cyclophosphamide, doxorubicin hydrochloride, and vincristine sulfate [Oncovin; CHOP].1 It was [therapies like] the proMACE-cytaBOM [cyclophosphamide, doxorubicin, etoposide, cytarabine, bleomycin, vincristine, methotrexate, prednisone, leucovorin, and co-trimoxazole]...that had improved progression-free survival [PFS], and not a single one improved overall survival [OS], but they were all more toxic than CHOP.1

When we look at polatuzumab vedotin [Polivy] plus bendamustine [Bendeka] and rituximab [Rituxan; Pola-BR] it also has a better PFS, but we have no data on improved OS and the same could be said for dose-adjusted rituximab-etoposide phosphate, vincristine sulfate, cyclophosphamide, doxorubicin hydrochloride, and prednisone [R-EPOCH].2,3 [Pola-BR is] going to give you a better complete response [CR] rate and the data would suggest PFS improvements in most subgroups, but no change in survival in phase 3 [studies]. And I don’t think it’s wrong to do Pola-BR, but it’s not a given, and I’m not moved off the blocks to switch everybody to it but some people are.... It’s certainly still reasonable and one of the reasons it’s still an option [under the National Comprehensive Cancer Network (NCCN) guidelines].

NCCN recommendations for [patients with DLBCL] at stage I early disease would be R-CHOP.4 At stage II with extensive mesenteric disease or stage III-IV—so your more advanced-stage patients—the preferred regimens are R-CHOP, R-CHP, and dose-adjusted R-EPOCH, which are all very reasonable. We also have several other regimens for those patients with cardiac dysfunction [as well as DLBCL], and we’re all aware of these regimens. I would say we’re aware of the limited data that suggest that the infusion of anthracyclines may be less cardiotoxic [for patients],5 although we haven’t really proved that in any good large studies.

LONG-TERM DATA SHOWING EFFECTIVENESS OF COMBINATION THERAPY

The original approval of the tafasitamab [Monjuvi] plus lenalidomide [Revlimid] combination from the FDA [was due to the] 1-year data from the L-MIND study,6 but now the 5-year data...[have shown] that in those patients with 2 or more prior lines of therapy, the overall response rates [ORRs] were 47.5% [95% CI, 31.5%-63.9%] with a 30% CR rate.7

If they had just 1 prior line of therapy that failed them, the CR rate is about 52.5% with an ORR of 67.5% [95% CI, 45.9%-79.4%].7 If we think about the patient in this [case] who progressed at 8 months and wanted to get therapy at home, and declined chimeric antigen receptor [CAR] T-cell therapy, compared with other chemotherapy options [these data are] encouraging to me when we look at the 5-year results, because there’s a meaningful chance of a true CR [ for the patient]. Now that’s nice but what we’re really looking for is durability, and the median duration of response [DOR] at the 5-year follow-up...is not met [95% CI, 33.8-not reached (NR)].7

[To answer the] question of are we curing some of these people—only if they fall into the subgroup of a full remission, and we have 5-year data that have over 50% [of patients] still in remission....7 We have a lot of patients [receiving] CAR T-cell therapy [who are] still progressing but there’s a thought that some of them might be cured, and maybe with this immunotherapy there’s that similar idea but I don’t know. But certainly, if you have a patient [receiving] tafasitamab/lenalidomide and they get a remission [with the therapy], then you can tell the patient if they’re in that group then there is more than a 50% chance they’re going to maintain that remission beyond 5 years, and that’s awfully encouraging from my perspective.

Now, CRs are still important, but if we [can get the patient to] have a long survival with stable disease for this patient population, that’s ideal, and that’s the kind of data we have with a 5-year follow-up here. Again, [in patients for whom] 1 prior line of therapy [ failed] vs 2 or more,… there was certainly a difference [in their follow-up and OS results] at median follow-up of 57.6 months [95% CI, 26.5-60.7] vs 33.9 months [95% CI, 10.9-46.8], respectively.7 In the final 5-year data, the median OS was NR [95% CI, 24.6-NR] if the patient had 1 prior line of therapy, and if they had 2 or more prior lines then the median OS was 15.5 months [95% CI, 8.6-45.5].6 Again, the point of this would suggest PFS improvements in most subgroups, but no change in survival in phase 3 [studies]. And I don’t think it’s wrong to do Pola-BR, but it’s not a given, and I’m not moved off the blocks to switch everybody to it but some people are.... It’s certainly still reasonable and one of the reasons it’s still an option [under the National Comprehensive Cancer Network (NCCN) guidelines].

NCCN recommendations for [patients with DLBCL] at stage I early disease would be R-CHOP.4 At stage II with extensive mesenteric disease or stage III-IV—so your more advanced-stage patients—the preferred regimens are R-CHOP, R-CHP, and dose-adjusted R-EPOCH, which are all very reasonable. We also have several other regimens for those patients with cardiac dysfunction [as well as DLBCL], and we’re all aware of these regimens. I would say we’re aware of the limited data that suggest that the infusion of anthracyclines may be less cardiotoxic [for patients],5 although we haven’t really proved that in any good large studies.

LONG-TERM DATA SHOWING EFFECTIVENESS OF COMBINATION THERAPY

The original approval of the tafasitamab [Monjuvi] plus lenalidomide [Revlimid] combination from the FDA [was due to the] 1-year data from the L-MIND study,6 but now the 5-year data...[have shown] that in those patients with 2 or more prior lines of therapy, the overall response rates [ORRs] were 47.5% [95% CI, 31.5%-63.9%] with a 30% CR rate.7

L-MIND efficacy at 5-year follow-up

If they had just 1 prior line of therapy that failed them, the CR rate is about 52.5% with an ORR of 67.5% [95% CI, 45.9%-79.4%].7 If we think about the patient in this [case] who progressed at 8 months and wanted to get therapy at home, and declined chimeric antigen receptor [CAR] T-cell therapy, compared with other chemotherapy options [these data are] encouraging to me when we look at the 5-year results, because there’s a meaningful chance of a true CR [for the patient]. Now that’s nice but what we’re really looking for is durability, and the median duration of response [DOR] at the 5-year follow-up...is not met [95% CI, 33.8-not reached (NR)].7

[To answer the] question of are we curing some of these people—only if they fall into the subgroup of a full remission, and we have 5-year data that have over 50% [of patients] still in remission....7 We have a lot of patients [receiving] CAR T-cell therapy [who are] still progressing but there’s a thought that some of them might be cured, and maybe with this immunotherapy there’s that similar idea but I don’t know. But certainly, if you have a patient [receiving] tafasitamab/lenalidomide and they get a remission [with the therapy], then you can tell the patient if they’re in that group then there is more than a 50% chance they’re going to maintain that remission beyond 5 years, and that’s awfully encouraging from my perspective.

Now, CRs are still important, but if we [can get the patient to] have a long survival with stable disease for this patient population, that’s ideal, and that’s the kind of data we have with a 5-year follow-up here. Again, [in patients for whom] 1 prior line of therapy [ failed] vs 2 or more,… there was certainly a difference [in their follow-up and OS results] at median follow-up of 57.6 months [95% CI, 26.5-60.7] vs 33.9 months [95% CI, 10.9-46.8], respectively.7 In the final 5-year data, the median OS was NR [95% CI, 24.6-NR] if the patient had 1 prior line of therapy, and if they had 2 or more prior lines then the median OS was 15.5 months [95% CI, 8.6-45.5].6 Again, the point of this therapy was to [have the patient] stay on therapy until it failed them, but a lot of people stopped treatment for a variety of reasons. But when they did stop many still maintained a remission that was quite durable [through the 5-year mark], but it wasn’t everybody who maintained it.7

ADDRESSING TOXICITIES

[Now the tafasitamab/lenalidomide had] nice efficacy results at 5 years, but is it toxic? Are these people going to be able to stay home, receive outpatient care, and have a good quality of life? Looking at the treatment-emergent adverse events [TEAEs] across all treatments, including TEAEs from the combined therapy or lenalidomide, there were 851 any-grade nonhematologic TEAEs and 345 hematologic TEAEs [over the entirety of 5 years]. Looking at the tafasitamab monotherapy given for up to 2 years, when you drop the lenalidomide the nonhematologic toxicities go down quite significantly to 383 events, which is probably not surprising, and beyond 2 years even lower at 347 events.

With the hematologic toxicities, you should primarily expect neutropenia... and with the combined therapy, that was the biggest TEAE for us to manage [with 49.4% of patients experiencing any-grade neutropenia, 48.1% of which was grade 3 or greater].7 For the monotherapy— these were the patients who were able to stay on therapy with some dosing of lenalidomide—the majority [of patients] went down to under 20 events and stayed at their same dose level.

Once [the lenalidomide is] dropped you still get some neutropenia...but very few high-grade cases, and occasionally beyond 2 years of tolerating treatment this well, again [it] is uncommon. The most common [any-grade nonhematologic TEAEs] during the combination phase were diarrhea [37.0%], asthenia [25.9%], and peripheral edema [24.7%].7 Once the lenalidomide was dropped, and then beyond 2 years of monotherapy, there were very few nonhematologic toxicities encountered.

Now,…we forget that lenalidomide still has a whole package insert for us to worry about. So I think concerns regarding renal function issues in these patients are appropriate concerns, and many of the patients do have to have a dose reduction of lenalidomide. I do think in those first 3 treatment cycles it’s every week they’re coming in and they have to get some therapy if they choose therapy, but still having logistics and support is important [in case that changes]. Having them get back and forth and having that support can be a little bit difficult.

REFERENCES

1. Rojek AE, Smith SM. Evolution of therapy for limited stage diffuse large B-cell lymphoma. Blood Cancer J. 2022;12(2):33. doi:10.1038/s41408-021-00596-z

2. Sehn LH, Hertzberg M, Opat S, et al. Polatuzumab vedotin plus bendamustine and rituximab in relapsed/refractory DLBCL: survival update and new extension cohort data. Blood Adv. 2022;6(2):533-543. doi:10.1182/bloodadvances.2021005794

3. Major A, Smith SM. DA-R-EPOCH vs R-CHOP in DLBCL: how do we choose? Clin Adv Hematol Oncol. 2021;19(11):698-709.

4. NCCN. Clinical Practice Guidelines in Oncology. B-cell lymphomas, version 1.2024. Accessed January 25, 2024. https://bit.ly/3TEXEqA

5. Teixeira da Silva F, Morais Passos R, Esteves A, Carvalho J, Ferreira M. Anthracycline cardiotoxicity in a patient with diffuse large B-cell lymphoma: a case report. Cureus. 2020;12(10):e11038. doi:10.7759/ cureus.11038

6. FDA grants accelerated approval to tafasitamab-cxix for diffuse large B-cell lymphoma. Updated August 3, 2020. Accessed January 25, 2024. http://tinyurl. com/774sy3d3

7. Duell J, Abrisqueta P, Andre M, et al. Tafasitamab for patients with relapsed or refractory diffuse large B-cell lymphoma: final 5-year efficacy and safety in the phase II L-MIND study. Haematologica. Published online August 31, 2023. doi:10.3324/ haematol.2023.283480

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